Novel Combinations Dominate Later-Line Metastatic CRC Treatment Landscape

Thorvardur (Thor) Halfdanarson, MD, discusses novel approaches under investigation in the later-line treatment of patients with CRC.

The emergence of combination regimens in the field of colorectal cancer (CRC) over the years has resulted in substantial improvements in the prognosis of patients with the disease, according to Thorvardur (Thor) Halfdanarson, MD.

“For subsequent lines of therapy, what has changed in recent years is that we're not thinking as rigidly about the different lines of therapy,” said Halfdanarson, a professor of oncology and associate professor of medicine, Division of Medical Oncology and medical oncologist with Mayo Clinic. “[We are thinking of this] more like a continuum of therapy, where we start with a more aggressive sort of induction therapy, followed by maintenance therapy, and then followed by the intensification of therapy again, as well as molecularly-directed therapy.”

With regard to targeted combinations, the BEACON CRC trial examined encorafenib (Braftovi) plus cetuximab (Erbitux) with or without binimetinib (Mektovi) in previously treated patients with BRAF V600E–mutated CRC and showed improved overall survival (OS) and objective response rates (ORRs) compared with standard chemotherapy alone.1 The median OS was 9.3 months with the triplet, 9.3 months with the doublet, and 5.9 months with the control regimen; the confirmed ORRs were 27%, 20%, and 2%, respectively.

“This is probably the most notable among some of the later-line trials that have been done in the space,” noted Halfdanarson.

Smaller trials are also examining immunotherapy combinations for heavily pretreated patients with advanced disease. For example, the phase 1b REGONIVO trial is examining regorafenib (Stivarga) in combination with nivolumab (Opdivo) in patients with advanced CRC or gastric cancer who had received a median of 3 prior lines of therapy.2 Early data showed promising antitumor activity with the approach.

The role of immunotherapy continues to evolve, according to Halfdanarson. “It is safe to say that, so far, there is not a well-defined role [for this in those with microsatellite stable disease], but recent studies have looked at checkpoint inhibitor combinations, as well as a combination of checkpoint inhibitors with targeted therapies,” he said. “I would say that's an evolving field.”

In an interview with OncLive® during the Institutional Perspectives on Cancer webinar on Gastrointestinal Cancers, Halfdanarson further discussed novel approaches under investigation in the later-line treatment of patients with CRC.

OncLive®: What are some of the latest updates in the field of CRC?

Halfdanarson: [One] of the notable studies that has recently read out in the frontline setting examined the use of the immunotherapy pembrolizumab (Keytruda) in patients with mismatch repairdeficient CRC; these data were presented at the 2020 ASCO Virtual Scientific Program and they were certainly practice changing.

Among some of the later-line trials, probably most notable in terms of targeted therapy, would be the work that was done for patients with BRAF-mutated tumors.The[phase 3] BEACON CRC trial examined the BRAF inhibitors with encorafenib plus cetuximab [with or without binimetinib] in patients with BRAF V600E-mutant CRC.

I should also mention some recent intriguing, but smaller, immunotherapy trials, such as the REGONIVO trial, which is looking at the combination of regorafenib plus nivolumab. Also, another recently published study examined trifluridine/tipiracil (TAS-102; Lonsurf) with bevacizumab (Avastin) in later lines of therapy.

You mentioned that immunotherapy trials are generating excitement in CRC. Could you expand on how the role of this approach has evolved in recent years?

[The role of immunotherapy] is evolving, but it’s safe to say that it is obviously the treatment of choice for patients with mismatch repair deficient (dMMR) metastatic CRC, for any line of therapy.

We have known for several years now that pembrolizumab and other checkpoint inhibitors are effective in that population of patients. One recent change is that we're testing patients earlier; we now test at the time of diagnosis for metastatic disease. Actually, many of these patients will have been tested at the diagnosis of early-stage disease. This information is often available when metastases develop later. 

As for later lines of therapy and checkpoint inhibitors in patients with metastatic mismatch repair proficient or microsatellite stable tumors, [the role of immunotherapy] is less clear.

What are the genomic differences between left- versus right-sided tumors? How does tumor location impact your treatment decisions?

As for the sidedness and the molecular differences, it has been known for a long time that right-sided tumors are more likely to be BRAFmutated. Also, we know that [patients with] BRAF-mutated tumors have a very poor prognosis compared with those who have BRAF wild-type tumors. More recently, it has also been confirmed that not all the BRAF-mutated tumors are created equal. Different mutations exist, and the most common one is BRAF V600E, but other BRAF mutations may be associated with prognosis in a different way and not all of them are associated with an inferior prognosis.

As for the dMMR tumors, this is where there's an interesting paradox. In general, right-sided tumors have a worse prognosis; that has been seen now in several trials; they are also more likely to be dMMR, although that ends up [accounting for] a relatively small proportion of right-sided tumors, in general. That small [subgroup of [patients with] right-sided tumors actually do quite well with immunotherapy.

What approaches are under investigation for patients who don't harbor genomic alterations?

For patients who don't harbor genomic alterations, we are unfortunately still largely use systemic chemotherapy. However, we’re now also looking at drugs that affect the VEGF pathways, so the inclusion of bevacizumab with TAS-102 [is considered]. There was also a study of fruquintinib, which has shown some promise in a Chinese trial and is now being tested in the United States, and then there is regorafenib in combination with immunotherapy.

Could you expand on some of the novel approaches that are under investigation in the third-line setting?

Several different trials [are ongoing right] now, most notably—at least at our center—is a study of the VEGF inhibitor fruquintinib, which has been shown to be somewhat promising in studies done outside of the United States.

Other studies are underway that are looking at the combination of immunotherapy with other multikinase inhibitors that also look promising for other tumor types, but we'll have to see how that all pans out for CRC.

What are some remaining challenges that still need to be addressed?

There are still challenges [within the field of CRC]. If you look at the overall survival (OS) of patients with metastatic CRC, it has certainly improved remarkably in the past 15 to 20 years. Still, most patients will eventually succumb to the disease and there are, unfortunately, not many 5-year survivors with metastatic CRC. We have extended the OS, but we still need to do better and increase the number of patients surviving at 5 years.

What are some key messages you would like to add?

There is ongoing improvement in the management of patients with metastatic CRC. For most of these patients, there hasn’t been a great leap forward; however, if you look at the benefits over the past 15 to 20 years, the progress is incremental.

What I sometimes tell my colleagues, especially those who are a little bit frustrated about the lack of major breakthroughs in the management of CRC, is that you actually have to take a step back and look at where we were 15 to 20 years ago to really see where we are today. If you compare those survival numbers you will see that there have actually been substantial improvements in the prognosis of these patients [over the years].


  1. Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J Clin Oncol. 2020;38(suppl 15):4001. doi:10.1200/JCO.2020.38.15_suppl.4001
  2. Shitara K, Hara H, Takahashi N, et al. Updated results from a phase 1b trial of regorafenib plus nivolumab in patients with advanced colorectal or gastric cancer (REGONIVO, EPOC1603). J Clin Oncol. 2020;38(suppl 4):135.